This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this project we propose the development of small molecule inhibitors of the HIV Vif protein. While Vif has been recognized as an important gene for viral infectivity, the cellular mechanism responsible for this effect has only recently been elucidated. Vif functions to inactivate the cellular defense protein APOBEC 3G which otherwise induces deamination of viral DNA rendering it noninfectious. Our previous work in vaccine development has demonstrated the crucial in vivo significance of Vif to viral replication in the rhesus macaque and supports the relevance of this drug target. The University of Massachusetts Medical School (UMMS) established a high throughput drug screening facility in order to identify lead compounds with activity against HIV/SIV Vif. As part of this venture, a large chemical library has been screened for anti-Vif compounds using a cell-based inhibitor screen and a number of lead compounds have been identified that have the potential to target peripheral and CNS reservoirs of HIV-1 replication and persistence. The proposed work will facilitate the further development of these Vif inhibiting agents. Rodent and nonhuman primate studies will use a three tier approach consisting of: 1) toxicity and pharmacokinetic studies to define drug candidate dose, vehicle and route;2) short term efficacy studies to evaluate effect on peripheral viral load;and 3) long term efficacy studies to evaluate the effect on SIV encephalitis.